Hypertension, which affected around 26.4% of the global adult population in 2000 and was projected to affect 29.2% by 2025 (Kearney et al., 2005, Lancet. 365:217-223), is the major controllable risk factor associated with cardiovascular disease (CVD) events such as myocardial infraction, stroke, heart failure, and end-stage diabetes. A 5-mmHg reduction in blood pressure has been equated with around 16% reduction in CVD (FitzGerald et al., 2004, J. Nutr. 134: 980S-988S). The seventh Joint National Committee (JNC 7) reported the risk of heart disease and stroke increases at blood pressure above systolic blood pressure (SBP)/diastolic blood pressure (DBP) values of 115/75 mmHg. JNC 7 recommended that the pre-hypertensive individuals (SBP 120-139 mmHg or DBP 80-89 mmHg) adopt health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD. Therefore, the awareness of and demand for functional food ingredients or nutraceuticals for controlling blood pressure have been raised globally.
Many bioactive peptides derived from milk proteins have been found to have health-enhancing nutraceutical potential. These peptides directly influence numerous biological processes, exhibiting antimicrobial, antithrombotic, immunomodulatory, mineral carrier, opioid-like, or angiotensin I-converting enzyme (ACE) inhibitory activities (Clare and Swaisgood, 2000, J. Dairy Sci. 83: 1187-1195). Among the bioactive peptides, ACE inhibitory peptides have attracted particular attention and have been studied most comprehensively for their applications to prevent hypertension, an independent risk factor for CVD (Li et al., 2004, Nutr. Res. 24: 469-486). ACE is a multifunctional ectoenzyme located in different tissues and plays a key physiological role in renin-angiotesin, kallikrein-kinin, and immune systems. The enzyme is responsible for the increase in blood pressure by converting angiotensin-I to the potent vasoconstrictor, angiotensin-II, and by degrading bradykinin, a vasodilatory peptide, and enkephalins. Inhibition of ACE is considered to be a useful therapeutic approach in the treatment of hypertension. To date, several adverse side effects such as hypotension, increased potassium levels, reduced renal function, cough, angioedema, skin rashes, and fetal abnormalities have been associated with the ACE inhibitory drugs. However, the ACE inhibitory peptides naturally derived from food protein sources are considered to be milder and safer without the side effects associated with the drugs.
In the development of novel functional food for controlling pressure, many ACE inhibitory peptides derived from milk proteins have been found (Yamamoto et al., 1994, J. Dairy Sci. 77: 917-922; Maeno et al., 1996, J. Dairy Sci. 79: 1316-1321; Yamamoto, 1997, Biopoly. 43: 129-134; Pihlanto-Leppälä et al. 1998, Int. Dairy J. 8: 325-331; Yamamoto and Takano, 1999, Nahrung 43: 159-164; Clare and Swaisgood, 2000, ut supra; Minervini et al., 2003, Appl. Environ. Microbiol. 69: 5297-5305; Li et al., 2004, ut supra; Robert et al., 2004, J. Agric. Food Chem. 52: 6923-6931; and Quirós et al., 2005, J. Dairy Sci. 88: 3480-3487). However, most of these peptides have not yet been confirmed in vivo. Only some of the ACE inhibitory peptides have been shown to exhibit antihypertensive activities in spontaneously hypertensive rats (SHRs) (FitzGerald et al., 2004, ut supra). To date, there are several products, such as Calpis sour milk drink (Calpis Co., Japan) and C 12 peptide (DMV International, The Netherlands), on the market in the form of fermented milk or milk protein hydrolysates. In these cases, the active antihypertensive peptides including IPP, VPP, and FFVAPFEVFGK have been identified. However, there is still a great demand for antihypertensive peptides that may be administered orally in a minor dosage.